The present invention relates to compounds that modulate the PPARxcex3 receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof) and inflammatory disorders.
The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally identified as orphan receptors, without known ligands, but were named for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid: metabolism has provided insight into regulation of energy homeostasis in vertebrates,;and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
PPARxcex3 is one member of the nuclear receptor superfamily of ligand-activated transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARxcex3 plays a pivotal role in the adipogenic signaling cascade. PPARxcex3 also regulates the ob/leptin gene which is involved in regulating energy homeostasis, and adipocyte differentiation which has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
In an effort to understand the role of PPARxcex3 in adipocyte differentiation, several investigators have focused on the identification of PPARxcex3 activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PPARxcex3-selective ligands. More recently, compounds that selectively activate murine PPARxcex3 were shown to possess in vivo antidiabetic activity in mice.
Despite the advances made with the thiazolidinedione class of antidiabetes agents, unacceptable side effects have limited their clinical use. Accordingly, there remains a need for potent, selective activators of PPARxcex3 which will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and energy homeostasis. Still further, compounds that block PPARxcex3 activity would be useful for interfering with the maturation of preadipocytes into adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable adipocyte maturation. Surprisingly, the present invention provides compounds that are useful as activators as well as antagonists of PPARxcex3 activity and compositions containing them, along with methods for their use.
In one aspect, the present invention provides methods of modulating conditions which are mediated by PPARxcex3 . The methods typically involve contacting the host with a PPARxcex3-modulating amount of a compound having the formula: 
in which the symbol Ar1 represents an aryl group; the letter X represents a divalent linkage selected from the group consisting of xe2x80x94(C1-C6)alkylene, xe2x80x94(C1-C6)alkylenoxy, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94N(R11)C(O)xe2x80x94, xe2x80x94S(O)kxe2x80x94 and a single bond, in which R11 is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl and arylalkyl and the subscript k is an integer of from 0 to 2. The letter Y, in the above formula represents a divalent linkage selected from the group consisting of alkylene, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94N(R13)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, a single bond, and combinations thereof in which R12 and R13 are members independently selected from the group consisting of hydrogen, alkyl, heteroalkyl and arylalkyl; and the subscripts m and n are independently integers of from 0 to 2.
The symbol R1 represents a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, xe2x80x94CO2R14, xe2x80x94C(O)R14, xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94S(O)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94OR17, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17 and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94OR17, in which R14 is a member selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and arylalkyl, and R15 and R16 are members independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, and arylalkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring. The symbol R17 represents a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl. Additionally, for the R1 groups described above, the subscript p is an integer of from 0 to 3, and the subscript q is an integer of from 1 to 2.
The symbol R2 represents a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl.
In another aspect, the present invention provides compounds of the formula above, as well as pharmaceutical compositions containing the compounds described above.